The present invention is directed to an apparatus and method of imaging and treatment using at least one photodynamic therapy (xe2x80x9cPDTxe2x80x9d) agent. In particular, the apparatus and method is for imaging and treating diseased tissue.
Imaging is typically performed to locate diseased tissue or tumors in a body. Once the diseased tissue is located, it is subsequently treated in some manner in order to destroy the diseased cells within this tissue. As explained infra, in the past, these were two separate procedures in a long, drawn out process that was frequently unsuccessful.
Imaging is generally performed using an imaging device such as CAT (Computerized Axial Tomography) scan or MRI (Magnetic Resonance Imaging). Alternatively, fluorography (using an image produced on a fluorescent screen by x-rays) or similar procedures can be used. Each of these imaging procedures requires a contrast agent for optimal performance. Examples of such imaging contrast agents include iodinated agents such as Omnipaque(trademark) (Iohexol) and Omniscan(trademark) (Gadodiamide) for x-ray based imaging or one of the various paramagnetic MRI contrast agents like gadolinium DPTA (Gd-DPTA).
Once the diseased tissue has been located via imaging, it needs to be treated. Such treatments, however, are often unsuccessful.
All current therapies for cancer (e.g., radiation and chemotherapy) function by attacking rapidly proliferating cells. Unfortunately, this targeting criterion does not limit the effects of treatment to cancer cells. As a consequence, such therapies are accompanied by undesirable side effects that may be life threatening. Furthermore, such therapies may actually reduce natural anti-tumor defenses. For example, radiation and chemotherapy damage the rapidly dividing cells of the immune system, suppressing anti-tumor and anti-infection responses.
Besides producing undesirable side effects, current therapies are largely incapable of achieving the desired potency of effects since they do not specifically attack cancer cells. Consequently, radiation or chemotherapy alone or in combination rarely cures cancer. Thus, the primary treatment for cancer is currently surgical removal of the tumor. This is commonly paired with adjuvant radiation and chemotherapy. Hence, to achieve a cure, the patient is surgically mutilated and poisoned by highly toxic treatments in an effort to destroy all cancer cells.
In an effort to minimize invasiveness of cancer treatment and improve overall efficacy, photodynamic therapy (PDT) has been developed. Photodynamic therapy is the combination of a photosensitive agent with site-specific illumination to produce a therapeutic response in certain tissues, such as a tumor. The agent attains an excited state when it absorbs a photon, and then is or becomes efficacious. Unfortunately, conventional single-photon excitation (SPE) methods used for the illumination step in PDT have not allowed PDT to reach its potential, primarily because (1) the high-energy light required for such treatment is incapable of penetrating deeply into tissue and (2) such illumination affords the physician with minimal spatial control of the treatment site. In contrast, the low-energy light used for two-photon excitation (TPE) PDT can safely penetrate tissue and provides three-dimensional control of treatment margins.
A more detailed explanation of TPE and SPE is provided in commonly owned U.S. Pat. No. 5,829,448, which is incorporated herein by reference.
While the use of two-photon excitation in PDT substantially ameliorates the depth of penetration and spatial control issues plaguing conventional PDT, additional improvements can be achieved by improvement of therapeutic performance of PDT agents and improvement of disease specificity in the selection of activation site. This is the consequence of several shortcomings of currently used agents and activation targeting approaches.
The only major PDT agent licensed by the Food and Drug Administration in the United States is the Type-II agent, porfimer sodium (or PHOTOFRIN(trademark)). This porphyrin-based agent is representative of a family of related agents (such as benzoporphyrin-derivative, SnEt2, and Lutex) that are commonly activated via single-photon methods using light between 500 nm and 730 nm in wavelength. Such Type-II agents produce a therapeutic effect through the light-activated conversion (photocatalytic conversion) of oxygen into an unstable and toxic form (singlet oxygen) that destroys biological material. Unfortunately, this mechanism requires a rich supply of oxygen at the treatment site. This supply, however, can be quickly depleted, for example due to compromised blood supply (as is common in the center of a large tumor) or intense illumination (which can consume all available oxygen, preventing continued conversion into singlet oxygen). Thus, treatment of large tumors and the use of aggressive illumination methods are not practical with such agents. Further, agents like porfimer sodium must typically be administered systemically (via intravenous injection) at high dose levels well in advance of illumination (typically at least 24 hours in advancexe2x80x94increasing cost and inconvenience to the patient). Moreover, the high doses required for systemic administration are very expensive (up to $5,000 or more per dose) and cause persistent skin photosensitization.
The problems with porphyrin-based agents stem in part from the fact that these agents fail to achieve significant concentration in tumors. Rather, large doses administered systemically saturate all tissues. As a result, after a clearance time in the range of hours to days, single-photon excitation of residual agent at the treatment site produces not only the desired cytotoxic effect in the diseased tissue but can also damage healthy surrounding tissue by activation of the agent present there as well. It is this residual agent that also accounts for persistent skin photosensitization. Moreover, this family of agents is typified by relatively high toxicity without light activation (dark cytotoxicity). Light activation generally increases this toxicity only marginally (poor light-to-dark cytotoxicity ratio). While use of two-photon excitation can improve the performance of PDT with such agents, specifically by reducing or eliminating potential collateral damage during illumination, coupling TPE with an agent having improved biotargetting and light-to-dark cytotoxicity would dramatically enhance the safety and efficacy of PDT.
However, the ability to realize such advantages requires that the size, location and depth of the target be known precisely so that the light used for TPE can be precisely delivered to the target. Therefore, a new method that allows tumors or other diseased tissues to be identified and located quickly and precisely is required. Additional characteristics of such a method should solve other current problems with PDT, including: improved light-to-dark cytotoxicity ratio for the agent (and more specifically a very low dark cytotoxicity); improved accumulation of agent into diseased tissue with strong contrast between diseased and healthy tissue; and capability of combining imaging and therapy (such as through photoactivation of the agent in imaged locations). Further characteristics should include significantly reducing the cost of the agent and rapidly clearing the agent from normal tissue.
Therefore, it is an object of the present invention to meet these characteristics and to overcome the drawbacks in prior methods and agents.
The present invention is directed to a method and apparatus for imaging and treating diseased tissue using at least one PDT agent.
One embodiment of the method of the present invention includes the steps of administering a photo-active agent, the photo-active agent being retained in diseased tissue; and treating the diseased tissue with light sufficient to photo-activate the photo-active agent in the diseased tissue.
Preferably, the photo-active agent is a halogenated xanthene such as Rose Bengal.
A further embodiment of the method of the present invention includes the steps of administering a photo-active agent to a patient prior to or following imaging, the photo-active agent being retained in the diseased tissue; imaging the patient to identify the diseased tissue; and treating the imaged diseased tissue with light sufficient to photo-activate the photo-active agent in the imaged diseased tissue.
In a further embodiment, the photo-active agent is capable of acting as a contrast agent for CAT scanning, fluorography or related procedures.
In a further embodiment, the photo-active agent is capable of acting as a contrast agent for CAT scanning, fluorography or related procedures and being photo-activated in the diseased tissue.
In a further embodiment, the photo-active agent is capable of acting as a contrast agent for MRI and being photo-activated in diseased tissue.
In still a further embodiment, the photo-active agent is mixed with MRI, CAT scan, fluorography or related targeting or contrast agents prior to use.
In another embodiment of the present invention, the light source for performing PDT is integrated into or attached to an imaging device (e.g., CAT scan, MRI, or related devices). In a further embodiment, the method uses a light source in the combined PDT/imaging apparatus which causes two-photon excitation. In an alternative embodiment, the light source in the combined PDT/imaging apparatus causes single photon excitation.